Method for treating erectile dysfunction

ABSTRACT

Levosimendan, or (−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, which has been previously suggested for the treatment of congestive heart failure, is useful in the treatment of erectile dysfunction.

This application is a U.S. national stage filing of PCT InternationalApplication No. PCT/FI01/01101, filed on Dec. 14, 2001. This applicationalso claims the benefit of priority under 35 U.S.C. § 119(a) to Finnishpatent application no. 20002755, filed on Dec. 15, 2000.

TECHNICAL FIELD

The present invention relates to a method for the treatment of erectiledysfunction by administering levosimendan, or(−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile(I), or pharmaceutically acceptable salts thereof, to a patient in needof such treatment.

BACKGROUND OF THE INVENTION

Levosimendan, which is the (−)-enantiomer of[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile,and the method for its preparation is described in EP 565546 B1.Levosimendan is potent in the treatment of heart failure and hassignificant calcium dependent binding to troponin. Levosimendan isrepresented by the formula:

The hemodynamic effects of levosimendan in man are described inSundberg, S. et al., Am. J. Cardiol., 1995; 75: 1061–1066 and inLilleberg, J. et al., J. Cardiovasc. Pharmacol., 26(Suppl.1), S63–S69,1995. Pharmacokinetics of levosimendan in man after i.v. and oral dosingis described in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol.,26(Suppl.1), S57–S62, 1995. The use of levosimendan in the treatment ofmyocardial ischemia is described in WO 93/21921. The use of levosimendanin the treatment of pulmonary hypertension is described in WO 99/66912.Transdermal delivery of levosimendan is described in WO 98/01111.Transmucosal delivery of levosimendan is described in WO 99/32081.Clinical studies have confirmed the beneficial effects of levosimendanin heart failure patients.

Erectile dysfunction is the inability to obtain and sustain sufficientpenile erection and is referred to as impotence. It can result from avariety of underlying causes ranging from purely psychogenic tocompletely physical dysfunctioning. Both surgical and pharmacologicaltherapies have been used in the treatment of impotence.

SUMMARY OF THE INVENTION

It has now been found that levosimendan is capable of restoring orimproving the erectile function in patients suffering from erectiledysfunction.

Therefore, the present invention provides the use of levosimendan or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of erectile dysfunction.

The present invention also provides a method for the treatment oferectile dysfunction in a patient, said method comprising administeringto a patient in need thereof an effective amount of levosimendan or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

The method of the invention comprises a step of administering to asubject an amount of levosimendan effective to restore the erectilefunction of the patient. The drug is preferably administered perorally,transmucosally including transurethrally, intravenously, intramuscularlyincluding intracavernosal injection or transdermally. The administrationmay be systemic or local.

The effective amount of levosimendan to be administered to a subjectdepends upon the route of administration. Levosimendan is administeredorally to man in daily dose from about 0.1 to 15 mg, preferably fromabout 0.5 to 10 mg, given once a day or divided into several doses aday. For transmucosal, intravenous, intramuscular or transdermaldelivery the daily dose range is from about 0.005 to 0.7 mg/kg,preferably from about 0.01 to 0.5 mg/kg.

Levosimendan is formulated into dosage forms suitable for the treatmentof erectile dysfunction using the principles known in the art. It isgiven to a patient as such or preferably in combination with suitablepharmaceutical excipients in the form of tablets, dragees, capsules,suppositories, emulsions, suspensions or solutions whereby the contentsof the active compound in the formulation is from about 0.5 to 100% perweight. Choosing suitable ingredients for the composition is a routinefor those of ordinary skill in the art. It is evident that suitablecarriers, solvents, gel forming ingredients, dispersion formingingredients, antioxidants, colours, sweeteners, wetting compounds,release controlling components and other ingredients normally used inthis field of technology may be also used.

For oral administration in tablet form, suitable carriers and excipientsinclude e.g. lactose, corn starch, magnesium stearate, calcium phosphateand talc. For oral administration in capsule form, useful carriers andexcipients include e.g. lactose, corn starch, magnesium stearate andtalc. Disintegrants, such as croscarmellose sodium, may be used toaccelerate the dissolution of the formulation.

Tablets can be prepared by mixing the active ingredient with thecarriers and excipients and compressing the powdery mixture intotablets. Capsules can be prepared by mixing the active ingredient withthe carriers and excipients and placing the powdery mixture in capsules,e.g. hard gelatin capsules. Typically a tablet or a capsule comprisesfrom about 0.1 to 10 mg, more typically 0.2 to 5 mg, of levosimendan. Ingeneral, rapidly dissolving peroral tablets or capsules, e.g. having adissintegration time of 1 to 20 minutes, are preferred.

Formulations suitable for intravenous administration such as injectionformulation, comprise sterile isotonic solutions of levosimendan andvehicle, preferably aqueous solutions. Typically an intravenous infusionsolution comprises from about 0.01 to 0.1 mg/ml of levosimendan.

Formulations of levosimendan suitable for transmucosal or transdermaladministration are disclosed in WO 99/32081 and WO 98/01111,respectively.

Salts of levosimendan may be prepared by known methods. Pharmaceuticallyacceptable salts are useful as active medicaments, however, preferredsalts are the salts with alkali or alkaline earth metals.

EXAMPLES

Pharmaceutical example. Hard gelatin capsule size 3 Levosimendan 2.0 mg Lactose 198 mg The pharmaceutical preparation in the form of a capsule was prepared bymixing levosimendan with lactose and placing the powdery mixture in hardgelatin capsule.

Clinical Data

Two NYHA III heart failure patients, who had not had erections forseveral years were treated with levosimendan. Patient I was exposed to0.05 μg/kg/min continuous infusion of levosimendan for 7 days. Thepatient reported erections 1 day after starting the infusion and he haderections in the mornings during the whole study. Patient II reportederections after 0.1 μg/kg/min continuous infusion of levosimendan for 2days.

The invention claimed is:
 1. A method for the treatment of erectiledysfunction in a patient, said method comprising orally administering toa patient in need thereof an effective amount of levosimendan or apharmaceutically acceptable salt thereof.
 2. A method as claimed inclaim 1, which comprises administering levosimendan or apharmaceutically acceptable alkali or alkaline earth metal salt oflevosimendan to the patient.
 3. A method as claimed in claim 1, whichcomprises orally administering an effective amount of levosimendan tothe patient.
 4. A method as claimed in claim 1, which comprises orallyadministering an effective amount of a pharmaceutically acceptable saltof levosimendan to the patient.